P38 Mitogen-activated Protein Kinase- and HuR-dependent Stabilization of P21(Cip1) MRNA Mediates the G(1)/S Checkpoint

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2009 Jun 17

PMID 19528229

Citations 142

Authors

Vanesa Lafarga

Ana Cuadrado

Isabel Lopez de Silanes

Rocio Bengoechea

Oscar Fernandez-Capetillo

Angel R Nebreda

Affiliations

Soon will be listed here.

Abstract

Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G(2)/M cell cycle arrest induced by DNA damage, but little is known about the role of this signaling pathway in the G(1)/S transition. Upregulation of the cyclin-dependent kinase inhibitor p21(Cip1) is thought to make a major contribution to the G(1)/S cell cycle arrest induced by gamma radiation. We show here that inhibition of p38 MAPK impairs p21(Cip1) accumulation and, as a result, the ability of cells to arrest in G(1) in response to gamma radiation. We found that p38 MAPK induces p21(Cip1) mRNA stabilization, without affecting its transcription or the stability of the protein. In particular, p38 MAPK phosphorylates the mRNA binding protein HuR on Thr118, which results in cytoplasmic accumulation of HuR and its enhanced binding to the p21(Cip1) mRNA. Our findings help to understand the emerging role of p38 MAPK in the cellular responses to DNA damage and reveal the existence of p53-independent networks that cooperate in modulating p21(Cip1) levels at the G(1)/S checkpoint.

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References

Fan X, Steitz J . Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J. 1998; 17(12):3448-60. PMC: 1170681. DOI: 10.1093/emboj/17.12.3448. View

Waldman T, Lengauer C, Kinzler K, Vogelstein B . Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature. 1996; 381(6584):713-6. DOI: 10.1038/381713a0. View

Kim H, Abdelmohsen K, Lal A, Pullmann Jr R, Yang X, Galban S . Nuclear HuR accumulation through phosphorylation by Cdk1. Genes Dev. 2008; 22(13):1804-15. PMC: 2492667. DOI: 10.1101/gad.1645808. View

Rotman G, Shiloh Y . ATM: from gene to function. Hum Mol Genet. 1998; 7(10):1555-63. DOI: 10.1093/hmg/7.10.1555. View

Cayrol C, Ducommun B . Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21. Oncogene. 1998; 17(19):2437-44. DOI: 10.1038/sj.onc.1202189. View

Abdelmohsen K, Pullmann Jr R, Lal A, Kim H, Galban S, Yang X . Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Mol Cell. 2007; 25(4):543-57. PMC: 1986740. DOI: 10.1016/j.molcel.2007.01.011. View

Di Micco R, Fumagalli M, dAdda di Fagagna F . Breaking news: high-speed race ends in arrest--how oncogenes induce senescence. Trends Cell Biol. 2007; 17(11):529-36. DOI: 10.1016/j.tcb.2007.07.012. View

Zhou B, Liao Y, Xia W, Spohn B, Lee M, Hung M . Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol. 2001; 3(3):245-52. DOI: 10.1038/35060032. View

Harris S, Levine A . The p53 pathway: positive and negative feedback loops. Oncogene. 2005; 24(17):2899-908. DOI: 10.1038/sj.onc.1208615. View

10.

Ambrosino C, Mace G, Galban S, Fritsch C, Vintersten K, Black E . Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase. Mol Cell Biol. 2002; 23(1):370-81. PMC: 140674. DOI: 10.1128/MCB.23.1.370-381.2003. View

11.

Taher M, Hershey C, Oakley J, Valerie K . Role of the p38 and MEK-1/2/p42/44 MAP kinase pathways in the differential activation of human immunodeficiency virus gene expression by ultraviolet and ionizing radiation. Photochem Photobiol. 2000; 71(4):455-9. DOI: 10.1562/0031-8655(2000)071<0455:rotpam>2.0.co;2. View

12.

Keene J . Why is Hu where? Shuttling of early-response-gene messenger RNA subsets. Proc Natl Acad Sci U S A. 1999; 96(1):5-7. PMC: 33538. DOI: 10.1073/pnas.96.1.5. View

13.

Wang W, Furneaux H, Cheng H, Caldwell M, Hutter D, Liu Y . HuR regulates p21 mRNA stabilization by UV light. Mol Cell Biol. 2000; 20(3):760-9. PMC: 85192. DOI: 10.1128/MCB.20.3.760-769.2000. View

14.

Jascur T, Brickner H, Salles-Passador I, Barbier V, El Khissiin A, Smith B . Regulation of p21(WAF1/CIP1) stability by WISp39, a Hsp90 binding TPR protein. Mol Cell. 2005; 17(2):237-49. DOI: 10.1016/j.molcel.2004.11.049. View

15.

Zeng Y, El-Deiry W . Regulation of p21WAF1/CIP1 expression by p53-independent pathways. Oncogene. 1996; 12(7):1557-64. View

16.

Jin S, Kim T, Yang K, Kim W . Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR. Eur J Pharmacol. 2007; 558(1-3):14-20. DOI: 10.1016/j.ejphar.2006.11.060. View

17.

Schwaller J, Koeffler H, Niklaus G, Loetscher P, Nagel S, Fey M . Posttranscriptional stabilization underlies p53-independent induction of p21WAF1/CIP1/SDI1 in differentiating human leukemic cells. J Clin Invest. 1995; 95(3):973-9. PMC: 441429. DOI: 10.1172/JCI117806. View

18.

Lafarga V, Cuadrado A, Nebreda A . p18(Hamlet) mediates different p53-dependent responses to DNA-damage inducing agents. Cell Cycle. 2007; 6(19):2319-22. DOI: 10.4161/cc.6.19.4741. View

19.

Briata P, Forcales S, Ponassi M, Corte G, Chen C, Karin M . p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP controls the stability of select myogenic transcripts. Mol Cell. 2005; 20(6):891-903. DOI: 10.1016/j.molcel.2005.10.021. View

20.

Hickson I, Zhao Y, Richardson C, Green S, Martin N, Orr A . Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004; 64(24):9152-9. DOI: 10.1158/0008-5472.CAN-04-2727. View